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Modulation of the p75 neurotrophin receptor using LM11A-31 prevents diabetes-induced retinal vascular permeability in mice via inhibition of inflammation and the RhoA kinase pathway

Published on May 9, 2019in Diabetologia 7.11
· DOI :10.1007/s00125-019-4885-2
Sally L Elshaer5
Estimated H-index: 5
(Mansoura University),
Sally L. Elshaer1
Estimated H-index: 1
(Mansoura University)
+ 4 AuthorsAzza B. El-Remessy2
Estimated H-index: 2
(Charlie Norwood VA Medical Center)
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Abstract
Aims/hypothesis Breakdown of the inner blood–retinal barrier (BRB) is an early event in the pathogenesis of diabetic macular oedema, that eventually leads to vision loss. We have previously shown that diabetes causes an imbalance of nerve growth factor (NGF) isoforms resulting in accumulation of its precursor proNGF and upregulation of the p75 neurotrophin receptor (p75NTR), with consequent increases in the activation of Ras homologue gene family, member A (RhoA). We also showed that genetic deletion of p75NTR in diabetes preserved the BRB and prevented inflammatory mediators in retinas. This study aims to examine the therapeutic potential of LM11A-31, a small-molecule p75NTR modulator and proNGF antagonist, in preventing diabetes-induced BRB breakdown. The study also examined the role of p75NTR/RhoA downstream signalling in mediating cell permeability.
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Published on Jan 16, 2019in ACS Chemical Neuroscience 3.86
Zhen Xu1
Estimated H-index: 1
,
Wei-Hua Shi1
Estimated H-index: 1
(Nantong University)
+ 4 AuthorsQun Hou1
Estimated H-index: 1
Early brain injury (EBI) after aneurysmal subarachnoid hemorrhage (SAH) contributes to high morbidity and mortality. Although it is well recognized that acute neuroinflammation reaction is one of the most important triggers of EBI, pharmacotherapy proved to be clinically effective against the initiating of neuroinflammation after SAH is lacking. The resident microglia and infiltrated peripheral monocyte are two main types of immune cells in central nervous system (CNS) and control the inflammati...
Published on Dec 1, 2018in Scientific Reports 4.01
Sally L. Elshaer1
Estimated H-index: 1
(UT: University of Tennessee),
Azza B. El-Remessy2
Estimated H-index: 2
(Charlie Norwood VA Medical Center)
Ischemic retinopathy is characterized by ischemia followed by retinal neovascularization (RNV) resulting in visual impairment. Given the role of neuron-secreted growth factors in regulating angiogenesis, we examined how genetic deletion of the neurotrophin receptor; p75NTR can overcome retinal ischemia using oxygen-induced retinopathy (OIR) mouse model. Wildtype (WT) or p75NTR−/− mice pups were subjected to hyperoxia (70% O2, p7-p12) then returned to normal air (relative hypoxia, p12-p17). Vascu...
Published on Aug 15, 2018in Human Molecular Genetics 4.54
Danielle A. Simmons8
Estimated H-index: 8
(Stanford University),
Michelle L. James19
Estimated H-index: 19
(Stanford University)
+ 7 AuthorsFrank M. Longo49
Estimated H-index: 49
(Stanford University)
Published on Apr 1, 2018in EBioMedicine
Volatiana Rakotoarivelo3
Estimated H-index: 3
(Université de Sherbrooke),
Gregory Lacraz3
Estimated H-index: 3
(Université de Sherbrooke)
+ 7 AuthorsSheela Ramanathan18
Estimated H-index: 18
(Université de Sherbrooke)
Abstract Population studies have linked insulin resistance to systemic low-grade chronic inflammation and have reported elevated levels of inflammatory cytokines such as TNFα, IL-1β and IL-6, individually or in certain combinations, in adipose tissues or in the serum. We undertook this comprehensive study to simultaneously evaluate the expression of several pro-inflammatory and anti-inflammatory cytokines in serum and in the visceral and subcutaneous adipose tissues from obese patients undergoin...
Published on Mar 1, 2018in Biochimica et Biophysica Acta 3.79
Riyaz Mohamed13
Estimated H-index: 13
,
Maha Coucha10
Estimated H-index: 10
+ 3 AuthorsA.B. El–Remessy37
Estimated H-index: 37
Abstract Impaired maturation of nerve growth factor precursor (proNGF) and its accumulation has been reported in several neurodegenerative diseases, myocardial infarction and diabetes. To elucidate the direct impact of proNGF accumulation identified the need to create a transgenic model that can express fully mutated cleavage-resistant proNGF. Using Cre-Lox technology, we developed an inducible endothelial-specific proNGF transgenic mouse (proNGF Loxp ) that overexpresses GFP-conjugated cleavage...
Published on Sep 1, 2017in RMD Open
Gaetana Minnone6
Estimated H-index: 6
(Boston Children's Hospital),
Marzia Soligo6
Estimated H-index: 6
+ 7 AuthorsLuisa Bracci-Laudiero22
Estimated H-index: 22
Objective To identify the role of mature nerve growth factor (mNGF), its immature form proNGF and their receptors in arthritis inflammation. Methods Real-time PCR, western blot and ELISA were performed to evaluate NGF, proNGF, their receptor and cytokine expression in synovial tissue and cells of patients with juvenile idiopathic arthritis (JIA) and rheumatoid arthritis (RA), and controls. Results proNGF and not mNGF is the prevalent form measured in synovial fluids of patients with JIA and RA w...
Published on Jun 29, 2017in Antioxidants
Sally L Elshaer5
Estimated H-index: 5
,
Islam N. Mohamed7
Estimated H-index: 7
(UGA: University of Georgia)
+ 6 AuthorsA.B. El–Remessy37
Estimated H-index: 37
(UGA: University of Georgia)
Background: Previous work demonstrated that high-fat diet (HFD) triggered thioredoxin-interacting protein (TXNIP) and that silencing TXNIP prevents diabetes-impaired vascular recovery. Here, we examine the impact of genetic deletion of TXNIP on HFD-impaired vascular recovery using hind limb ischemia model. Methods: Wild type mice (WT, C57Bl/6) and TXNIP knockout mice (TKO) were fed either normal chow diet (WT-ND and TKO-ND) or 60% high-fat diet (WT-HFD and TKO-HFD). After four weeks of HFD, unil...
Published on Jun 1, 2017in Investigative Ophthalmology & Visual Science 3.81
Lindsay Rountree2
Estimated H-index: 2
(Cardiff University),
Pádraig J. Mulholland4
Estimated H-index: 4
(NIHR: National Institute for Health Research)
+ 3 AuthorsTony Redmond11
Estimated H-index: 11
(Cardiff University)
Purpose : Guided by changes in spatial summation in glaucoma, we undertook a cross-sectional prospective study to compare disease signal, response variability, and signal/noise ratio (SNR) between perimetric stimuli varying in area, contrast, and both simultaneously, in patients with glaucoma and age-similar healthy controls. Methods : Participants were 30 glaucoma patients (median [interquartile range] age: 70.4 years [66.2, 73.5], MD: -4.04dB [-9.65, -2.85]) and 20 controls (age: 69.3 years [6...
Published on Mar 4, 2017in Expert Review of Ophthalmology
Sally L. Elshaer1
Estimated H-index: 1
(Charlie Norwood VA Medical Center),
Azza B. El-Remessy2
Estimated H-index: 2
(Charlie Norwood VA Medical Center)
ABSTRACTIntroduction: The p75 neurotrophin receptor (p75NTR) is a member of TNF-α receptor superfamily that bind all neurotrophins, mainly regulating their pro-apoptotic actions. Ischemia is a common pathology in different cardiovascular diseases affecting multiple organs, however the contribution of p75NTR remains not fully addressed. The aim of this work is to review the current evidence through published literature studying the impact of p75NTR receptor in ischemic vascular diseases. Areas co...
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